Method for the production of lowtoxic surface anaesthetics



United States Patent 3,038,835 METHOD FOR THE PRODUCTION OF LGW- TOXICSURFACE ANAESTHETICS Giinther Endres and Klaus Seehring, Hamburg,Germany,

and Fritz Henn, Bofors, Sweden, assignors to Aktiebolaget Bofors,Bofors, Sweden, a company of Sweden No Drawing. Filed June 28, 1960,Ser. No. 39,211

Claims priority, application Sweden July 1, 1959 8 Claims. (Cl. 167-52)The purpose of the present invention is to create a new surfaceanaesthetic which has a low toxicity.

It is previously known to use injectable local anaesthetics as surfaceanaesthetics. Examples of such are procaine, tetracaine, hostacaine,lidocaine and carbocaine. The last-mentioned compound has the followingformula:

(II) R4 O -NH in which R designates a straight branched or cyclichydrocarbon chain with a maximum of eight carbon atoms,

in which R designates hydrogen or a hydrocarbon chain with a maximum oftwo carbon atoms,

in which R, designates hydrogen or a hydrocarbon chain with a maximum oftwo carbon atoms, R and R, then together having not more than threecarbon atoms, and

in which R R are chosen among hydrogen groups, alkyl groups with amaximum of two carbon atoms, R R then together having not more than fourcarbon atoms.

A common characteristic. for the said injectable local anaesthetics isthat they are toxic to a certain extent. When they are to be used assurface anaesthetics on for instance skin and mucous membranes, it cansometimes occur that they are to be used on large surfaces, and largequantities will then be required. It is then desirable that theconcentration of the local anaesthetic is kept as low as possible withconsideration to the toxicity. This involves that the duration isreduced considerably and in many cases does not attain the valuerequired. It is thus a desire to be able to increase the duration whilemaintaining a low toxicity. It is, consequently, the toxicity which setsthe upper limit for the duration of the injectable local anaesthetic. Itis not advisable to use concentrations of more than 4% withconsideration to the toxicity. It is known to use as a surfaceanaesthetic a compound called Thesit (hydroxy-polyethoxy-dodecane) andwith the general formula R-(OCH CH ),,OCH CH OH in which R designates analkyl, an aryl or an alkyl aryl group with a maximum of 20 carbon atomsand a minimum of 6 carbon atoms or preferably with a maximum of 16carbon atoms and a minimum of 8 carbon atoms, in which n has a valuelying between 4 and 16 or preferably between 6 and 14. The said compoundhas very little toxicity but iias the disadvantage that the depth ofthis anaesthetic is not satisfactory. The compound should not be used inconcentrations higher than 6%, as otherwise dermatological secondaryetfects can occur. In most cases it is recommendable not to useconcentrations lower than 2%. It is not advisable to exceed a molecularweight of 800 and not even to set a lower limit for the molecular weightthan 500. An appropriate relation between the number of carbon atoms inthe group R and the number of oxyethyl groups is about 4-3.

At the production of a compound according to the 3,038,835 Patented June12, 1962 general formula it proves that a mixture is obtained in a whichthe different components have values of n lying within the said limits.It is, of course, possible to separate a compound with the desired valueof n but as a rule the mixture is accepted in its existing state.

Tests have now shown that if, when using surface anaesthetics, aninjectable local anaesthetic or its salt are combined in a concentrationwhich keeps the toxicity within permissible limits with a surfaceanaesthetic according to the last-mentioned formula and in aconcentration which does not give rise to any secondary effects, asurface anaesthetic is obtained with an effect which exceeds the totaleffect of the two preparations. Tests have also shown that if aninjectable local anaesthetic is chosen in a concentration which does notcause surface anaesthesia and this is combined with a surfaceanaesthetic of the abovementioned formula, the combination preparationobtains an effect which as regards the toxicity is considerably higherthan that of the said surface anaesthetic.

The combination preparation formed is to be regarded as a mixture of thesaid injectable local anaesthetic and the said surface anaesthetic. Thetwo parts which have been mixed can be dissolved in an appropriatesolvent, for instance water, or can be mixed into an appropriate carrierso that an ointment, a gel or a tablet is obtained.

As the injectable local anaesthetics are very expensive and surfaceanaesthetics according to the formula are cheap to manufacture, a cheapand useful surface anaesthetic is obtained.

Concentrations of the components of the combination preparation can ofcourse be varied within wide limits on the condition that the toxicityof the combination preparation does not amount to such values that thepreparation is not appropriate as a surface anaesthetic.

The procedure according to the present invention will be illustratedthrough the following examples:

Example 1 0.25 g. of l-methyl-Z-piperidine carboxylic acid-2,6- dimethylanilide in a pulverized form and 0.25 g. of hydroxy ethoxy polyethoxydodecane in the form of an oil and with a molecular weight of approx.600 are dissolved in g. of distilled water with an isotonic addition ofsalt. The said mixture has the character of a liquid. If 0.25 ml. of thesaid liquid is placed on a rabbit cornea a duration of approx. 20minutes is obtained. A 0.25% solution of l-methyl-Z-piperidinecarboxylic acid-2,6-dimethyl anilide gives a duration of 0 when appliedto a rabbit cornea in a quantity of 0.25 A concentration of 0.25%hydroxy ethoxy polyethoxy dodecane when applied to a rabbit cornea andin a quantity of 0.25 ml. gives a duration of 10 minutes.

Example 2 If in Example 1, 0.25 g. of 1-methyl-2-piperidine carboxylicacid-2,6-dimethyl anilide is replaced by 0.50 g. ofl-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide a combinationpreparation is obtained which in a rabbit cornea gives a duration of21.2 minutes. A 0.50% solution of l-methyl-Z-piperidine carboxylicacid-2,6-dimethyl anilide gives a duration of 0 in a rabbit cornea.

Example 3 If in Example 1, 0.25 g. of l-methyl-Z-piperidine carboxylicacid-2,6-dimethyl anilide is replaced by 0.25 g. of w-diethylamino-2,6-dimethyl acetanilide, a combination preparation is obtainedwhich in a rabbit cornea gives a duration of 18.9 minutes. A 0.25%solution of w-diethyl amino-2,6-dimethyl acetanilide gives a duration of0 in a rabbit cornea test.

aoaasse Example 4 If in Example 1, 0.25 g. of l-methyl-Z-piperidinecarboxylic acid-2,6-dimethyl anilide is replaced by 0.10 g. of 2-diethylaminoethyl ester of p-aminobenzoic acid a combination preparation isobtainedwhich in a rabbit cornea test gives a duration of 18.4 minutes.A 0.1% solution of the said ester gives a duration of in a rabbit corneatest.

Example 5 If in Example 1, 0.25 g. of hydroxy ethoxy polyethoxy dodecaneis replaced by 0.25 g. of hydroxy ethoxy polyethoxy benzene acombination preparation is obtained which in a rabbit cornea test givesa duration of 14.5 minutes. A potentiation is obtained as theanaesthetics alone only give durations of 0 and 6.5 minutes,respectively.

Example 6 If in Example 1, 0.25 g. of hydroxy ethoxy polyethoxy dodecaneis replaced by 0.25 g. of hydroxy ethoxy polyethoxy octenyl dirnethylbenzene, a combination preparation is obtained which in a rabbit corneatest gives a duration of 15.3 minutes. A concentration of 0.25% ofhydroxy ethoxy polyethoxy octenyl dimethyl benzene gives a duration ofonly 4.5 minutes in the same test.

Example 7 If in Example 1 the injectable local anaesthetic is replacedby 01 g. of (1-cyclopentyl-2-piperidine carboxylic acid)2,6-dimethylanilide a combination preparation is obtained which in a rabbit corneatest gives a duration of 23.5 minutes. A potentiation is obtained as theanaesthetics individually give durations of only 3.0 and 6.5 minutes,respectively.

Example 8 If in Example 1 the injectable local anaesthetic is replacedby 0.1 g. of (1-methyl-5-ethyl-2-piperidine carboxylicacid)2,4,6-trimethyl anilide, a combination preparation is obtainedwhich in a cornea test gives a duration of 21.0 minutes. A potentiationis obtained, as the an aesthetics individually only give durations of 0and 6.5 minutes, respectively.

Tests have also shown that a 0.3% solution of hydroxy ethoxy polyethoxytetradecane can be combined with either 0.1% p-butylaminobenzoyl-dimethyl aminoethanol or with 0.2% n-butylamino2-methyl-6-chloroacetanilide, and a usable surface anaesthetic isthen obtained, the effect of which is approximately twice the effect ofthe hydroxy ethoxy polyethoxy tetradecane.

We claim:

1. A surface active anesthetic composition comprising a member of thegroup consisting of injectable local anesthetics and salts thereof and acompound having the formula wherein R designates a member of the groupconsisting of alkyl, aryl and alkylaryl having from 6 to 20 carbonatoms, and n is a whole number ranging from 4 to 16.

2. A surface active anesthetic composition in accordance with claim 1,wherein the local anesthetic is a member of the group consisting ofl-methyl-Z-piperidine carboxylic acid-2,6-dimethyl anilide,(l-cyclo-pentyl-Z-piperidine carboxylic acid)2,6-dimethyl anilide,(l-methyl-S- ethyl Z-piperidine carboxylic acid)2,4,6-trimethyl anilide,'w-diethyl amino-2,6-dimethyl acetanilide and Z-diethyl aminoethyl esterof p-amino benzoic acid.

3. A surface active anesthetic composition in accordance with claim 1,wherein the compound has a molecular weight'of about 500 to 800.

4. A surface active anesthetic composition in accordiance with claim 1,wherein the local anesthetic has the formula R R l H C-NHQ-Ru l Rz If RsR1 wherein:

R designates a saturated hydrocarbon radical having a maximum of 8carbon atoms;

R and R designate a member of the group consisting of hydrogen and analkyl group having a maximum of 2 carbon atoms, provided that R plus Rdoes not exceed 3 carbon atoms; and

R R R R and R are members of the group consisting of hydrogen and alkylradicals having a maximum of 2 carbon atoms, provided that the totalcarbon atoms in R plus R plus R plus R plus R does not exceed 4 carbonatoms.

5. Method of producing surface active anmthetic compositions of lowtoxicity which comprises mixing a member of the group consisting ofinjectable local anesthetics and salts thereof with a compound havingthe formula wherein R designates a member of the group consisting ofalkyl, aryl and alkylaryl having from 6 to 20 carbon atoms, and n is awhole number ranging from 4 to 16.

6. Method as defined in claim 5, wherein the local anesthetic is amember of the group consisting of lmethyLZ-Piperidine carboxylicacid-2,6-dimethyl anilide, (l-cyclo-pentyl-Z- iperidine car-boxylicacid)2,6-dimethyl anilide, (1-methyl-5-ethyl-2-piperidine carboxylicacid)- 2,4,6-trirnethyl anilide, w-diethyl amino-2,6-dimethylacetanilide and Z-diethyl aminoethyl ester of p-amino benzoic acid.

7. Method as defined in claim 5, wherein the compound has a molecularweight of about 500 to 800v 8. Method as defined in claim 5, wherein thelocal anesthetic has the formula R4 R5 i H C-NH Rn I R2 Rs R1 wherein:

R designates a saturated hydrocarbon radical having a maximum of 8carbon atoms;

R and R designate a member of the group consisting of hydrogen and analkyl group having a maximum of 2 carbon atoms, provided that R plus Rdoes not exceed 3 carbon atoms; and

R R R R and R are members of the group consisting of hydrogen and alkylradicals having a maximum of 2 carbon atoms, provided that the totalcarbon atoms in R plus R plus R plus R plus R does not exceed 4 carbonatoms.

References Cited in the file of this patent FOREIGN PATENTS 799,779Great Britain Aug. 13, 1958 799,780 Great Britain Aug. 13, 1958 805,523Great Britain Dec. 10, 1958 91,086 Norway Mar. 3, 1958 OTHER REFERENCESMonash: Arch. Dermatol, 1957, pp. 752-756.

Ellin et al.: J. Am. Pharm. Ass. Pract. Ed., 1955, pp. 747-9 Utsumi etal.: Chem. Abst., 51, 1957, 5831(c).

5. METHOD OF PRODUCING SURFACE ACTIVE ANESTHETIC COMPOSITIONS OF LOWTOXICITY WHICH COMPRISES MIXING A MEMBER OF THE GROUP CONSISTING OFINJEECTABLE LOCAL ANESTHETICS AND SALTS THEREOF WITH A COMPOUND HAVINGTHE FORMULA